The present invention relates to a class of tricyclic compounds that are useful as potassium channel inhibitors to treat autoimmune disorders and the like.
Immunoregulatory abnormalities have been shown to exist in a wide variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I and II diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, Graves ophthalmopathy and asthma.
Although the underlying pathogenesis of each of these conditions may be quite different, they have in common the appearance of a variety of autoantibodies and self-reactive lymphocytes. Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates. Similarly, following a bone-marrow or an organ transplantation, the host lymphocytes recognize the foreign tissue antigens and begin to produce antibodies which lead to graft rejection.
One end result of an autoimmune or a rejection process is tissue destruction caused by inflammatory cells and the mediators they release. Anti-inflammatory agents such as NSAID's act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease. On the other hand, cytotoxic agents, such as cyclophosphamide, act in such a nonspecific fashion that both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb from infection as they are from their autoimmune disease.
Cyclosporin A (CsA), which was approved by the US FDA in 1983 is currently the leading drug used to prevent rejection of transplanted organs. In 1993, FK-506 (Prograf) was approved by the US FDA for the prevention of rejection in liver transplantation. CsA and FK-506 act by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein. In 1994, CsA was approved by the US FDA for the treatment of severe psoriasis and has been approved by European regulatory agencies for the treatment of atopic dermatitis. Though they are effective in fighting transplant rejection, CsA and FK-506 are known to cause several undesirable side effects including nephrotoxicity, neurotoxicity, and gastrointestinal discomfort. Therefore, a selective immunossuppressant without these side effects still remains to be developed. Potassium channel inhibitors promise to be the solution to this problem.
The importance of potassium channels was first recognized almost fifty years ago when Hodgkin and Huxley discovered that potassium ions contributed to the current that excited the squid giant. Research in the area, however, was hampered by the lack of selective, high affinity ligands for potassium channels. But the advent of recombinant DNA techniques and single cell and whole cell voltage clamp techniques has changed the slow pace of the field. Potassium channels have turned out to be the most diverse family of ion channels discovered to date. They modulate a number of cellular events such as muscle contraction, neuro-endocrine secretion, frequency and duration of action potentials, electrolyte homeostasis, and resting membrane potential.
Potassium ion channels have been classified according to their biophysical and pharmacological characteristics. Salient among these are the voltage dependent potassium channels, such as K.sub.v 1. The K.sub.v 1 class of potassium channels is further subdivided depending on the function of the channel, for example K.sub.v 1.1, K.sub.v 1.3, K.sub.v 1.5. Functional voltage-gated K.sup.+ channels can exist as multimeric structures formed by the association of either identical or dissimilar subunits. This phenomena is thought to account for the wide diversity of K.sup.+ channels. However, subunit compositions of native K.sup.+ channels and the physiologic role that particular channels play are, in most cases, still unclear.
Membrane depolarization by K.sub.v 1.3 inhibition has been shown to be an effective method to prevent T-cell proliferation and therefore has applications in many autoimmune conditions. Inhibition of K.sup.+ channels in the plasma membrane of human T -lymphocytes has been postulated to play a role in eliciting immunosuppressive responses by regulating intracellular Ca.sup.++ homeostasis, which has been found to be important in T-cell activation.
The K.sub.v 1.3 voltage-gated potassium channel is found in neurons, blood cells, osteoclasts and T-lymphocytes. The Chandy and Cahalan laboratories proposed a hypothesis that blocking the K.sub.v 1.3 channel would elicit an immunosuppressant response. (Chandy et al., J. Exp. Med. 160, 369, 1984; Decoursey et al., Nature, 307, 465, 1984). However, the K+ channel blockers employed in their studies were non-selective. Until research with the peptide margatoxin, a peptide found in scorpion venom, no specific inhibitor of the K.sub.v 1.3 channel existed to test this hypothesis. Although a laboratory (Price et al., Proc. Natl. Acad. Sci. USA, 86, 10171, 1989) showed that charybdotoxin would block K.sub.v 1.3 in human T cells, charybdotoxin was subsequently shown to inhibit four different K.sup.+ channels (K.sub.v 1.3 and three distinct small conductance Ca.sup.++ activated K.sup.+ channels) in human T-lymphocytes, limiting the use of this toxin as a probe for the physiological role of K.sub.v 1.3 (Leonard et al., Proc. Natl. Acad. Sci. USA, 89, 10094, 1992). Margatoxin, on the other hand, blocks only K.sub.v 1.3 in T-cells, and has immunosuppressant activity in both in vitro and in vivo models. (fin et al., J. Exp. Med, 177, 637, 1993). The therapeutic utility of this compound, however, is limited by its potent toxicity. Recently, a class of compounds have been reported that may be an attractive alternative to the above-mentioned drugs, see for example U.S. Pat. Nos. 5,670,504; 5,631,282; 5,696,156; 5,679,705; and 5,696,156. While addressing some of the activity/toxicity problems of previous drugs, there is still a need to develop other compounds that would offer alternative treatments with differing toxicity profiles and patient tolerability.
Four active components of Spachea correa were recently identified which inhibit thymidine uptake of T cells. U.S. Pat. No. 5,631,282. ##STR1##
These compounds are useful as immunosuppressive agents in animals, including man. The present invention describes newly developed immunosuppressive compounds derived from the compounds described in Formulae 1(a) through 1(d) and which have the relative stereochemistry depicted above.